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Cushing's disease

About Cushing’s disease

Cushing’s disease is a rare pituitary disorder. Cushing’s disease is one of the causes of Cushing’s syndrome. Both are named for the famous neurosurgeon Harvey Cushing, and both relate to having too much cortisol in the body. Cortisol is a very important hormone that regulates the body’s metabolism, among other functions.

Cortisol is produced in the adrenal glands, which are small organs located above the kidneys. Though cortisol plays a critical role in good health, too much cortisol can have negative effects.

In Cushing’s disease, the problem begins in the pituitary gland. When your pituitary gland makes too much adrenocorticotropic hormone (ACTH), this sends the wrong message to your adrenal glands, which then make too much cortisol. This creates serious problems with your body’s hormone balance, causing a variety of symptoms.

At the OHSU Pituitary Center, we take care of a large number (about 200) of patients with Cushing’s disease, a very high volume for a rare disease. The director of the OHSU Pituitary Center, Maria Fleseriu, M.D., F.A.C.E., is a leading international expert who specializes in acromegaly and Cushing’s disease.

Cushing’s disease is caused by a pituitary adenoma (noncancerous tumor) that makes too much adrenocorticotropic hormone (ACTH). About 10 percent of pituitary adenomas are this type. Cushing’s disease is generally found in people between 20 to 50 years old. It affects women more than men, at roughly a 3-to-1 ratio.

Cushing’s disease can be difficult to diagnose because body changes can develop slowly. To decide a care plan, it is important to understand as much as possible about how much extra cortisol you have and where it is coming from within your body.

Sometimes, the symptoms and signs you are experiencing can relate to several medical disorders, so it’s important that we clearly determine that these issues are due to elevated adrenocorticotropic hormone (ACTH) and/or elevated cortisol levels that indicate Cushing’s disease. You will have tests that help determine if the extra cortisol or ACTH is coming from the pituitary or the adrenal glands.

For accurate tests, you should let us know if you are currently taking, or have recently taken, any steroid medications such as hydrocortisone, prednisone or dexamethasone, or are using any creams, inhalers or steroid injections that contain these ingredients. Women taking birth control pills may be asked to switch to a different type of birth control while undergoing testing.

The first step is a physical exam and a complete medical history. The next step is to measure the cortisol levels in the body.

Tests for Cushing’s disease include:

Screening tests
We use screening testing to help identify people with a high probability of Cushing’s syndrome/disease. Screening tests are minimally invasive. As Cushing’s syndrome is usually progressive, these tests may need to be repeated later if inconclusive. Initial tests may include:

Blood testsWe measure both the levels of adrenocorticotropic hormone (ACTH) and cortisol in your blood. However, the levels rise and fall over a 24-hour period, with the highest levels in the early morning, so we want to get a blood sample in that time frame. We may also give you a medication called dexamethasone to take at around 11 p.m. Then you will have a blood sample drawn for ACTH and cortisol first thing the next morning.

Urine testsWe may ask you to collect one or more 24-hour urine samples to measure the cortisol that you excrete in your urine. We will give you specific instructions for these collections that are important to follow closely to make sure the test results are accurate. You must note the exact time of the first early-morning collection. Then collect all urine throughout the day, ending exactly 24 hours after starting. You must keep the sample cool in your refrigerator or a cooler until delivered to the lab. If you are asked to collect two samples on two consecutive days, these must be kept in separate containers and timed accordingly. Check with us to see if any medications you are taking could affect these results.

Late-night saliva testCortisol may also be excreted in your saliva, so we will likely ask you to collect several samples at your bedtime, or between 11 p.m. and midnight. At this time of night, the cortisol levels usually drop to their lowest levels. Elevated cortisol levels at this time can suggest a diagnosis of Cushing’s syndrome. There are special instructions for collecting this test that we will give you in clinic.

Imaging

MRIYour referring provider may have previously ordered an MRI to determine if you have a pituitary tumor. This imaging can show the size and location of any mass in your pituitary. However, in Cushing’s disease, tumors may not be visible. If there are adequate views of the pituitary from the first scan, we will not repeat the MRI.

Abdominal CT scanIf there is the possibility of a tumor on your adrenal glands, we will recommend an abdominal CT scan. This is important to determine if a tumor is located on your right or left adrenal gland (or both). The scan can also show the characteristics of the tumor, which helps us determine your diagnosis. The radiology department will give you preparation instructions.

Dexamethasone suppression/corticotropic-releasing hormone stimulation test (DEX/CRH)If the screening tests suggest you have elevated ACTH/cortisol levels, we sometimes perform one more confirmatory test. We will give you a prescription for dexamethasone, a pill to take at certain times every six hours for two days. The morning you are scheduled for the test, you will get an IV in your arm both for your comfort and for accurate timing of blood draws. After we draw the initial blood samples (baseline samples) for ACTH, cortisol and dexamethasone levels, we will give you a dose of corticotropic-releasing hormone (CRH) through your IV. Most people have no issues with CRH, but you may feel a warming sensation. We will draw blood from the IV every 15 minutes for one hour to get the ACTH and cortisol samples. Results of this test may not be available for up to two weeks.

Inferior petrosal and cavernous sinus samplingIf the screening tests suggest excess ACTH is the cause of Cushing’s, the next step is to confirm if the source is pituitary or ectopic. This information is compared to your MRI images. For this test, we will give you sedation, so you will need to plan for someone to drive you home. Once you are sedated, we will place an IV in one arm and a thin tube (catheter) in your right and left groin. The specialist will then thread these catheters into an area known as the inferior petrosal or cavernous sinus, which is located on both sides of your pituitary gland. We will draw initial or baseline levels of ACTH from the IV and from both groin catheters. We will give you corticotropic-releasing hormone (CRH) through the IV in your arm. We will check the levels every one to two minutes over about six minutes. When the procedure is done, we will remove the groin catheters and apply a pressure dressing. Nurses will monitor your recovery in a specialized recovery area until you are ready to go home. If this test is positive, we will arrange for you to consult with our neurosurgeon. If results are negative, you may be referred to other specialists or your primary care provider for further evaluation of your symptoms.

Surgery

For most patients with Cushing’s disease, surgery is the initial treatment to remove the pituitary adenoma (noncancerous tumor) that is making too much adrenocorticotropic hormone (ACTH). Most pituitary tumors are removed through the nose in a procedure called transsphenoidal surgery (TSS). This approach leaves no obvious scars and has fewer side effects and risks. Patients often go home the day after surgery.

Removing the tumor can reduce ACTH secretion, allowing the pituitary to return to normal function and reducing the symptoms of Cushing’s.

Historically, surgeons often removed the adrenal glands as a solution for Cushing’s disease. Now, doctors prefer to attempt TSS, medication or radiation before surgically removing the adrenal glands. However, it is a treatment option that may be discussed depending on a number of factors for your condition.

Medication

For some people, surgery is not an option or doesn’t fully resolve the problem. Fortunately, scientists have made several breakthroughs in the last decade for treating pituitary adenomas with medication, resulting in several new therapies for Cushing’s disease. In fact, medication has moved to the forefront in treatment options for Cushing’s disease.

We use medication for Cushing’s disease:

Before surgery to control cortisol excess in some cases.

For people who can’t have surgery due to other health reasons or risks.

For people who have surgery, but the neurosurgeon couldn’t fully remove the tumor or the removal doesn’t resolve the problems.

For people who have too much ACTH, but a tumor doesn’t show on imaging.

For these patients, medication is the next course of action. Some people may need a combination of medications. Medications include:

Central-acting inhibitors of adrenocorticotropic hormone (ACTH)Pasireotide is a type of medication (abbreviated to SRLs for somatostatin receptor ligands) that is effective for about a quarter of the Cushing’s disease patients who use it to reduce ACTH to normal levels, and improves clinical features in many more. This medication is taken by injection and results can usually be seen within two months. There are several adverse events related to this medication, including hyperglycemia and diabetes in more than half of the patients.

Adrenal-directed inhibition of steroidogenesisThere are a number of medications in this category (metyrapone, mitotane, ketoconazole, etomidate, others), all off-label for Cushing’s, that target the adrenal glands rather than the pituitary to bring down the level of cortisol in the body. Remember, when your pituitary gland makes too much ACTH, this sends the wrong message to your adrenal glands, which then make too much cortisol. These drugs, in various ways, attempt to prevent the adrenal glands from producing too much cortisol. When choosing a specific drug, efficacy has to be balanced with the specific adverse events.

Glucocorticoid receptor blockadeApproved for use for hyperglycemia associated with Cushing’s syndrome in 2012, a medication called mifepristone can improve other conditions brought on by too much cortisol. The drug can induce hypokalemia and vaginal bleeding, and is contraindicated in women desiring pregnancy.

All drugs used for Cushing’s can potentially induce adrenal insufficiency and patients need close monitoring and treatment if this occurs. For more details on any drug’s efficacy and safety, please consult the FDA package insert.

The OHSU Pituitary Center is a national leader in research related to pituitary conditions. Our scientists were major contributors to clinical studies that resulted in FDA approval for mifepristone and pasireotide.

Radiation

Some people have an aggressive form of Cushing’s disease that may not respond to surgery and medication. In these cases, we may recommend radiation treatments to control cortisol. One method is through stereotactic radiosurgery, which uses precisely targeted radiation to reach any leftover or otherwise unreachable portions of the original tumor. Patients will require medication until radiation is able to control the ACTH secretion, and this might take more than five years.

Your team at the OHSU Pituitary Center will talk with you about the best treatment option for you.

With surgery, the success rate for small tumors (microadenomas) in a specialized center is approximately 80–85 percent. If the tumor has spread in the cavernous sinus, the success rate with surgery is much lower.

For patients who have successful surgery, your doctor will give you medication after surgery to replace the cortisol your body no longer makes. You may need replacement glucocorticoids for a long time, up to several months or years.

As follow-up, you will need regular examinations and tests by a pituitary expert to measure your hormone levels and to treat any medical conditions. This is necessary because the symptoms of Cushing’s can take time to go away. The doctors at the OHSU Pituitary Center will work with you to determine the best treatment and follow-up plan for you. You will also be tested for possible recurrence of Cushing’s disease, which can happen in about a quarter of patients.

Clinical trials are the last step in a lengthy process of research. These studies allow scientists to test the value of their research to diagnose, treat and prevent diseases and disabilities. Each clinical trial is an opportunity to test a promising invention or treatment.

The OHSU Pituitary Center is a national leader in research related to pituitary conditions. Our scientists were major contributors to clinical studies that resulted in two new, FDA-approved, ﬁrst-in-their-class treatments for Cushing’s disease: mifepristone and pasireotide.

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Surgical innovation and Cushing’s disease neuroimaging

OHSU neurosurgeon Justin Cetas, M.D., Ph.D., performs more than 100 surgeries annually for pituitary disorders, in addition to other brain surgeries. Drs. Cetas and Fleseriu are currently involved in a study to better identify small adrenocorticotropic hormone tumors in patients with Cushing’s disease.